Acute kidney injury (AKI) is a leading cause of chronic kidney disease. Proximal tubules are considered to be the primary origin of pathogenic inflammatory cytokines in AKI. However, it remains unclear whether other cell types, including collecting duct (CD) cells, participate in inflammatory processes. The transcription factor GATA2 is specifically expressed in CD cells and maintains their cellular identity. To explore the pathophysiological function of GATA2 in AKI, we generated renal tubular cell-specific Gata2 deletion (G2CKO) mice and examined their susceptibility to ischemia-reperfusion injury (IRI)...

Matrix metalloproteinase-9 (MMP-9) is dysregulated in chronic kidney diseases including diabetic nephropathy. This study was performed to examine the expression of MMP-9 in renal tubule epithelial cells (TECs) under diabetic conditions and its regulatory mechanisms. We characterized MMP-9 protein in diabetic animals and primary cultured rat TECs exposed to exogenous albumin and high glucose. We also used specific inhibitors to determine if internalization of albumin and/or extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation were required for MMP-9 secretion...

PURPOSE: Urea-based prostate-specific membrane antigen (PSMA) ligands labelled with (68)Ga or (177)Lu are new tracers with great potential for theranostic approaches in prostate cancer. However, clinical studies have shown that the kidneys are one of the off-target organs along with the salivary and lacrimal glands. In the kidneys, PSMA is physiologically expressed in the apical epithelium of the proximal tubules, and mannitol acts as an osmotic diuretic in these tubules. We investigated the potential of mannitol to reduce renal uptake of (68)Ga-PSMA...

Infiltration by IgG-positive plasma cells is a common finding in tubulointerstitial nephritis. Indeed, it has been thought that CD138-positive mature plasma cells secrete mainly IgG, and the occurrence of tubulointerstitial nephritis with CD138-positive plasma cells secreting IgM has rarely been reported. Routine immunofluorescence of fresh frozen sections is considered the gold standard for detection of immune deposits. However, the immunoenzyme method with formalin-fixed, paraffin-embedded sections is superior for detecting IgM- or IgG-positive cells within the renal interstitium, thus histologic variants may often go undetected...

Comprehensive transcriptome studies of cancers often rely on corresponding normal tissue samples to serve as a transcriptional reference. In this study, we performed in-depth analyses of normal kidney tissue transcriptomes from the TCGA and demonstrate that the histological variability in cellularity, inherent in the kidney architecture, lead to considerable transcriptional differences between samples. This should be considered when comparing expression profiles of normal and cancerous kidney tissues. We exploited these differences to define renal-cell-specific gene signatures and used these as a framework to analyze renal cell carcinoma (RCC) ontogeny...

The liver and the kidney are key toxicity target organs during drug development campaigns, as they typically carry the burden of drug transport and metabolism. Primary hepatocytes and proximal tubule epithelial cells grown in traditional in vitro 2-D culture systems do not maintain transporter and metabolic functions, thus limiting their utility for nonclinical toxicology investigations. We have developed a renal and hepatic microphysiological system (MPS) platform that uses a commercially available MPS device as the core cell culture platform for our methodologies...

Compared with males, females have lower BP before age 60, blunted hypertensive response to angiotensin II, and a leftward shift in pressure natriuresis. This study tested the concept that this female advantage associates with a distinct sexual dimorphic pattern of transporters along the nephron. We applied quantitative immunoblotting to generate profiles of transporters, channels, claudins, and selected regulators in both sexes and assessed the physiologic consequences of the differences. In rats, females excreted a saline load more rapidly than males did...

Novel renal replacement therapies, such as a bioartificial kidney (BAK), are needed to improve current hemodialysis treatment of end-stage renal disease (ESRD) patients. As BAK applications may reveal safety concerns, we assessed the alloimmunization and related safety aspects of readily available conditionally immortalized human proximal tubule epithelial cell (ciPTEC) lines to be used in BAK. Two ciPTEC lines, originally derived from urine and kidney tissue, were characterized for the expression and secretion of relevant molecules involved in alloimmunization and inflammatory responses, such as HLA class-I, HLA-DR, CD40, CD80, CD86, as wells as soluble HLA class I and proinflammatory cytokines (IL-6, IL-8 and TNF-α)...

Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor that reduces hyperglycemia in type 2 diabetes mellitus (T2DM) by promoting urinary glucose excretion (UGE). A clinical pharmacology study conducted in Japanese patients with T2DM confirmed dose-dependency of UGE with once-daily administration of luseogliflozin; however, the reason for sustained UGE after plasma luseogliflozin decreased was unclear. To elucidate the effect of inhibition rate constants, Kon and Koff, and to explain the sustained UGE, a pharmacokinetic-pharmacodynamic (PK-PD) model was built based on the mechanisms of glucose filtration in the glomerulus and reabsorption in the renal proximal tubule of kidney as well as the kinetics of competitive inhibition of SGLT1/2 and inhibition rate constants of SGLT2, by using UGE and plasma glucose levels and luseogliflozin concentrations...

Renal cell carcinoma (RCC), arising from the proximal tubule in the kidney, accounts for approximately 85% of kidney cancers and causes over 140,000 annual deaths worldwide. In the last decade, several new therapies have been identified for treatment of metastatic RCC. Although these therapies increase survival time compared to standard care, none of them has curative properties. The nephrotoxin orellanine specifically targets proximal tubular epithelial cells, leaving other organs unaffected. We therefore hypothesized that the selective toxicity of orellanine extends to clear cell RCC (ccRCC) cells since they emanate from proximal tubular cells...

AIM: Nephrilin peptide, a designed inhibitor of Rictor complex (mTORC2), exerts pleiotropic protective effects in metabolic, xenobiotic and traumatic stress models. Stress can generate enduring epigenetic changes in gene function. In this work we examine the possibility that nephrilin treatment protects against acute and enduring global changes in oxidative metabolism, with a focus on the Rictor-complex-mediated activation of Rac1, a subunit of NADPH oxidase (Nox) via PKCs, Prex1 and p66shc...

The formation of the proper number of nephrons requires a tightly regulated balance between renal progenitor cell self-renewal and differentiation. The molecular pathways that regulate the transition from renal progenitor to renal vesicle are not well understood. Here we show that Sall1interacts with the Nucleosome Remodeling and Deacetylase Complex (NuRD) to inhibit premature differentiation of nephron progenitor cells. Disruption of Sall1-NuRD in vivo in knock-in mice (ΔSRM) resulted in accelerated differentiation of nephron progenitors and bilateral renal hypoplasia...

In DM2, there is increased expression of the proximal glucose transporter SGLT2. The increased glucose reabsorption from the urine to the proximal tubule and subsequently to the bloodstream, has three direct effects on the prognosis of patients with DM2: a) it increases the daily glucose load by raising the renal threshold for glucose, thus augmenting requirements for oral antidiabetics and insulin. This progressive increase occurs throughout the course of the disease and in parallel with the increase in renal mass (renal hypertrophy); b) because of the greater glucose reabsorption, glycosuria is lower than the level corresponding to glycaemia, decreasing the stimulus on the tubuloglomerular feedback system of the distal nephron...

The kidney is involved in glucose homeostasis through three main mechanisms: renal gluconeogenesis, renal glucose consumption and glucose reabsorption in the proximal tubule. Glucose reabsorption is one of the most relevant physiological functions of the kidney, through which filtered glucose is fully recovered, urine is free of glucose, and calorie loss is prevented. Approximately 90% of the glucose is reabsorbed in the S1 segment of the proximal tubule, where GLUT2 and SGLT2 transporters are located, while the remaining 10% is reabsorbed in the S3 segment by SGLT1 and GLUT1 transporters...

BACKGROUND: T cell immunoglobulin and mucin domain 3 (TIM-3) is involved in alloimmune and autoimmune responses, as well as tolerance induction in kidney transplantation. Kidney injury molecule-1 (KIM-1) is highly expressed in epithelial cells of the injured proximal tubule. In this study, we have investigated both urinary and blood TIM-3 mRNA expressions, urinary KIM-1 mRNA expression, and urinary and serum KIM-1 proteins in renal allograft recipients diagnosed with acute allograft rejection (AR) and chronic allograft dysfunction (CAD), as well as those with well-functioning transplants (WFG)...

BACKGROUND: Although increased rates of vitamin B12 deficiency have been reported in patients with plasma cell dyscrasias (PCDs), no mechanism has been identified. Excess free light chains (FLCs) could disrupt the renal proximal tubule receptors where B12 is reabsorbed. We sought to characterize the relationship between B12 deficiency and PCDs. We hypothesized that rates of B12 deficiency would be highest in patients with PCDs with high FLC burdens. METHODS: We reviewed the electronic medical records of 501 patients who met inclusion criteria (diagnosed PCD with documented serum B12 and FLC levels) to obtain clinical data recorded prior to patients' lowest B12 levels...

Hepatocytes, renal proximal tubule cells as well as the highly specialized endothelium of the blood brain barrier (BBB) express and secrete apolipoprotein M (apoM). ApoM is a typical lipocalin containing a hydrophobic binding pocket predominantly carrying Sphingosine-1-Phosphate (S1P). The small signaling molecule S1P is associated with several physiological as well as pathological pathways whereas the role of apoM is less explored. Hepatic apoM acts as a chaperone to transport S1P through the circulation and kidney derived apoM seems to play a role in S1P recovery to prevent urinal loss...

Quinalphos or Ekalux, an organophosphate pesticide, is used in controlling the pests of a variety of crops. Quinalphos was studied on male Sprague-Dawley albino rats. The acute po LD50 of technical Ekalux was 19.95 mg/kg in males. Ekalux, produced several pathological changes in the kidney. A glomerulus demonstrated capillary lumina occluded by degenerated cellular debris. Basement membrane showed irregular wrinkling and branching. The proximal tubular cells showed damage such as dilation of endoplasmic reticulum, accumulation of glycogen granules, and pyknotic nucleus...

Adult-onset autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in either the PKD1 or PKD2 gene, leading to malfunction of their gene products, polycystin 1 or 2. Histone deacetylase 6 (HDAC6) expression and activity are increased in PKD1-mutant renal epithelial cells. Here we studied the effect of ACY-1215, a specific HDAC6 inhibitor, on cyst growth in ADPKD. Treatment with ACY-1215 slowed cyst growth in a mouse model of ADPKD that forms massive cysts within 3 weeks after knockout of polycystin 1 function...

Diabetic nephropathy is the leading cause of kidney failure. Treatments with drugs that block the renin-angiotensin system have proven beneficial in slowing kidney disease progression among those with diabetes; their benefit is limited and they do not stop disease progression. Despite multiple clinical trials of various interventions including dual blockade of the renin-angiotensin system over the past 15 years, no new therapies have emerged to slow kidney disease progression in diabetes. SGLT-2 inhibitors are a new class of antiglycemic drugs that have been shown to lower blood glucose by inhibition of the sodium-glucose transporter 2 in the proximal tubule of the kidney...